Acylamino-acyloxy-propionaphthones



Patented Mar. 13, 1951 UNITED STATES PATENT OFFICE ACYLAMINO-ACYLOXY-PRO- PIONAPHTHONES Loren M. Long, Grosse Pointe Woods, and Harvey ,D. Troutman, Ferndale, Mich., assignors to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Application January 21, 1950,

Serial No. 139,956

acyloxyethyl ketone compound having the formula, i p NHAcyl R,.| C-H-CHzOhmyl where n is l or 2 and R is the same or different and represents hydrogen, halogen, nitro, lower alk'yl or lower alkoxy radicals. The term acyl as used herein includes carboxylic acid acyl radicals, such as saturated and unsaturated lower aliphatic acyl, halogen substituted lower aliphatic acyl, carboxy substituted lower aliphatic acyl, cyano substituted lower aliphatic acyl, ether substituted lower aliphatic acyl, ester substituted lower aliphatic acyl, hydroxy substituted lower aliphatic acyl, benzoyl, substituted benzoyl, araliphatic acyl, furoyl, 'pyridinoyl and the like radicals.

In accordance with the invention, naphthyl a-acylamido fi-acyloxyethyl ketone compounds having the above formula are obtained by treating a naphthyl a-acylamido-p-hydroxyethyl ketone of formula,

NHAcyl with an acylating agent under substantially anhydrous conditions either alone or in the presence of an acylation cataylst, Where R and n have the same significance as given above. The transformation involved can be diagrammatically i1- lustrated as follows 8 Claims. (01. 260477) C) NHAcyl Rn C$HCH;OH

acylating agent (acylation catalyst) (3 NHAcyl R. -(JH-CH2OA0Y1 where R and n have the same significance as given above.

The conversion of the naphthyla-acylamidofl-hydroxyethyl ketone compounds to the corresponding p-acyloxy derivatives of the present invention can be effected by treating the B-hydroxy ketone compound with an acyl halide or acyl anhydride under substantially anhydrous conditions either alone or in the presence of an acylation catalyst such as an inorganic base, an alkaline salt of an organic acid, an organic tertiary base, an aromatic sulfonic acid or sulfuric acid. The acylation can, in general, be carried out at a temperature varying from about 10 to 140 C. but the preferred temperature for the reaction is between about and C. An inert organic solvent such as benzene, petroleum ether, toluene and the like can be used for the reaction if desired, although in most cases it is more expedient to omit the use of a solvent and to merely use an excess of the acylating agent. Some of the catalysts which can be used to bring about the reaction in a shorter period of time are sodium hydroxide, potassium hydroxide, potassium carbonate, sodium acetate, pyridine, quinoline, triethylamine, N-ethylmorpholine, N-methylpiperidine, N,N dimethylaniline, p toluenesulfonic acid and sulfuric acid.

The products of the invention are useful as intermediates in the preparation of other organic compounds. They are of particular value in preparation of organic compounds possessing unique antibiotic acitivity.

. r 3 The invention is illustrated by the following examples:

Example 1 20 g. of G-methyl 2 napththyl a-(p-toluylamide) 3-hydroxyethyl ketone is heated at about 75 C. for one-half hour with 40 cc. of acetic anhydride containing a very small amount of concentrated sulfuric acid. The reaction mixture is evaporated to dryness in vacuo, the residue Washed with ice water and purified by recrystallization from methanol or ethanol. The product thus obtained is S-methyl 2 naphthyl a- (p-toluylamido) -,6-acetoxyethyl ketone of the formula,

NH l@ CH. H

Emample 2 8 g. of 4-nitro-l-naphthyl a-acetamido-p-hydroxyethyl ketone is heated at about 60 C. for one-half hour with 20 cc. of acetic anhydride and 10 cc. of pyridine. The reaction mixture is evaporated to dryness in vacuo, the residue washed with ice water and purified by recrystallization from alcohol. The product thus obtained is 4-nitro-1-naphthyl a-acetamidofi-acetoxyethyl ketone of formula,

0 O NH-E-CHa H-CH2O-O-CH3 Example 3 20 g. of I-naphthyl a-benzamido-fi-hydroxyethyl ketone is heated at about 70 C. for one hour with 50 cc. of benzoyl chloride and 25 cc. of pyridine. The reaction mixture is evaporated to dryness in vacuo, the residue washed with ice water and purified by recrystallization from a1- cohol. The product thus obtained is l-naphthyl a-benzamido-p-benzoxyethyl ketone of formula,

O I (L H-CHzO-EQ Example 4 5 g. of Z-naphthyl a-cyanoacetamido-p-hydroxyethyl ketone is heated at about 65 C. for one hour with g. of furoic anhydride containing a very small amount of concentrated sulfuric acid. The reaction mixture is evaporated to dryness in vacuo, the residue washed with ice water and purified by recrystallization from methanol.

4 The product thus obtained is 2-naphthy1 a-cyano acetamido B-furoyloxyethyl ketone of formula,

Example 5 Example 6 10 g. of B-ethyl-l-naphthyl a-methoxypropionamido-fl-hydroxyethyl ketone is heated at about 75 C. for one-half hour with 10 g. of succinic anhydride containing a very small amount of concentrated sulfuric acid. The reaction mixture is evaporated to dryness in vacuo, the residue washed well with water and purified by recrystallization from methanol. The product thus obtained is 8-ethyl-l-naphthyl a-methoxypropicnamido-,B-succinoyloxyethyl ketone of formula,

Example -7 A mixture consisting of 45 g. of 4-nitro-1- naphthyl a-dichloroacetamido B hydroxyethyl ketone, g. of p-toluic anhydride and 18 g. of dry sodium acetate is heated at about45 C. while small amounts of ice and water-are added from time to time. After about one hour the mixture is diluted with 1 liter of water, cooled and adjusted to pH 8 with sodium hydroxide. The 4- nitro-l-naphthyl a-dichloroa'cetamido-fi-p toluyloxyethyl ketone which separates from the solution is collected, washed with water and dried. This product has the formula,

Example 8 20 g. of 4-bromo-1-naphthyl a-acetoxyyacetal Example 9 10 g. of 2-naphthyl a-nicotinamido-B-hydroxyethyl ketone is heated at about 70 C. for onehalf hour with 20 g. of fiuorocetic anhydride containing a very small amount of concentrated sulfuric acid. The reaction mixture is evaporated to dryness in vacuo, the residue washed with ice water and purified by recrystallization from methanol. The product thus obtained is 2- naphthyl anicotinamido B fluoroacetoxyethyl ketone of formula,

Example 10 r 20 g. of -chloro-l-naphthyl a-benzamido-phydroxyethyl ketone is heated at about 75 C. for one-half hour with 40 g. of crotonyl chloride con-- taining a very small amount of pyridine. The reaction mixture is evaporated to dryness in vacuo, the residue washed with ice water and purified by recrystallization from ethanol. The product thus obtained is 5-chloro-1-naphthyl a-benzamido-pcrotonyloxyethyl ketone of formula,

Example 11 A mixture of 10 g. of 6-iodo-1-naphthyl c furamido-B-hydroxyethyl ketone, 10 ml. ofbenzoyl chloride. 5 ml. of pyridine in ml. of dry benzene is refluxed for two hours. The mixture is cooled, concentrated in vacuo and the residue treated with 100 m1. of cold water. The oil which separates is extracted with ethyl ether and the organic extract is washed with dilute hydrochloric acid, water, dilute sodium bicarbonate solution and finally water. The dried ethereal layer is concentrated in vacuo and the residue is recrys-- tallized from ethyl alcohol. The product thus obtained is 6-iodo-1-naphthy1 afuramido-fi-benzoxyethyl ketone of formula,

Example 2 5 g. of l-naphthyl a-phenylacetamido-fi-hydroxyethyl ketone, 5 g. of phenylacetyl chloride, 2.5 ml. of pyridine and 50 ml. of dry benzene are refluxed for two hours. The mixture is concentrated in vacuo and the residue is treated with -toxyethyl ketone of formula,

Example 13 I u 0- H-CHnO-C-CHr-CHzO CHs Example 15 g. of *i-nitro-l-naphthyl a-dichloroacetamido-fi-hydroxyethyl ketone is heated at about 70 C. for one-half hour with 8 g. of dichloroacetic anhydride containing avery small amount of concentrated sulfuric acid. The reaction mixture is evaporated to dryness in vacuo, the residue washed with ice water and purified by recrystallization from methanol.

Example 16 A mixture of 5g. of 3,6-dichl0ro-l-naphthyl' a-benzamido-fi-hydroxyethyl ketone in g. of methyl lactateand 9.1 .g. ;of-p-to1uenesu1fonic acid is heated on the steam bath for three hours to effect complete removal of the methanol which is liberated in the reaction. The reaction mixture is evaporated to dryness in vacuo, the residue washed with ice water and purified by recrystallization from ethanol. The product thus obtained is 3.6-dichloro-l-naphthyl .a-benzamido-fi-a'-hydroxypropionyloxyethyl ketone of the formula,

Oi Oi Example 17 10 g. of -nitro-l-naphthyl a -dichloroaceta-- mido-fi-hydroxyethyl ketone isheatedat about 75 C. for one-half hour with ,cc. of acetic anhydride containing a very small amount of concentrated sulfuric acid. The reaction mixture is evaporated to dryness in vacuo. The residue The product thus obtained is 4-nitro-1-naphthyl .a-dichloroaceta- -mido-fi-dichloroacetoxyethyl ketone of formula,

8 is washed with ice water and purified by re:' crystallization from ethanol. The product thus obtained is 4-nitro-1-naphthy1 a-dichloroacetamido-li-acetoxyethyl ketone of the formula,

Example 18 A mixture of 10 g. of 1,8-dimethyl-2-naphthyl a-benzamido- 8-hydroxyethyl ketone, 10 ml. of benzoyl chloride, 5 ml. of pyridine in 100 ml. of

.dry benzene is refluxed for two hours. The mix ture is concentrated in vacuo and the residue'is treated withlOO ml. of cold water. The oil which separates is extracted with ethyl ether and the organic extract is Washed with dilute hydrochloric acid, water, dilute sodium bicarbonate solution and water. The dried ethereal layer is concentrated in vacuo and the residue is recrystallized from ethanol. The 1,8-dimethyl- Z-naphthyl o-benzamido-fibenzoyloxyethyl ketone which was thus obtained has the structure,

The naphthyl a-acylamido-fi-hydroxyethyl-ketone compounds used as startingmaterials in the practice of the invention can be preparedby the condensation of a naphthyl acylamidomethyl *ketone with formaldehyde in-the presence of an 7. alkaline condensation catalyst according to the process described and claimed in our co-pending application, Serial Number 139,955, filed under even date herewith. For example, l-naphthyl a-acetamido-fi-hydroxyethyl ketone, starting material'used in Example 1, can be prepared as follows:

60 g. of l-naphthyl acetamidomethyl ketone is mixed with 300 cc. of methanol and cc. of 40% formalin. 2 g. of sodium bicarbonate is added and the mixture is stirredat room temperature for about one hour. During this time the desired product separates. The insoluble l-naphthyl a-acetamido-,B-hydroxyethyl ketone of formula,

is collected and purified by recrystallization from ethyl acetate.

What We claim is: l. A compound of formula,

0 NHAcyl r 1 1 where n is one of the integers 1 and 2 and R is t r h d u NHAcyl a member of the class consis ing 0 y rogen,

1 halogen, nltro, lower alkyl and lower alkoxy CH CHOAW radicals.

2. A compound of formula, 5

0 NHAcyl C-CHOH2OAcy1 6. 4-nitro-1-naphthy1 a-acetamido-fi-acetoxyethyl ketone.

7. 4-nitro-1-naphthy1 a-dichloroacetamido-fiacetox eth 1 ketone. 3. l-naphthyl a-benzamido-fi-benzoy1oxyethyl y y 8. 4-nitro-l-naphthy1 a-dichloroacetamido-fiketone- 15 dichloroacetoxyethyl ketone.

4. l-naphthyl a phenyla am -fi- LOREN M. LONG. acetoxyethyl ketone. HARVEY TROUTMAN 5. A compound of formula,

No references cited. 

1. A COMPOUND OF FORMULA, 